Polyethylene Glycol Exposure with Antihemophilic Factor (Recombinant), PEGylated (rurioctocog alfa pegol) and Other Therapies Indicated for the Pediatric Population: History and Safety

Abstract

Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40–21,840 mg/year; for factor IX (FIX) products, the range was 13–1342 mg/year; and for other products, the range was 383–26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences.

Nanosized Delivery Systems for Therapeutic Proteins: Clinically Validated Technologies and Advanced Development Strategies

“…After repeated administration of some approved PEGylated biopharmaceuticals, cellular vacuolation were histologically observed in certain organs and tissues (Ivens et al, 2015). Vacuolation is considered a normal physiological process by which various cell types attempt to remove foreign materials (Stidl et al, 2018). In mammalian cells, vacuoles are formed in different cellular compartments (e.g., endosomes, lysosomes, endothelial reticulum), and this phenomenon can be transient or irreversible (Stidl et al, 2018).…”

“…Vacuolation is considered a normal physiological process by which various cell types attempt to remove foreign materials (Stidl et al, 2018). In mammalian cells, vacuoles are formed in different cellular compartments (e.g., endosomes, lysosomes, endothelial reticulum), and this phenomenon can be transient or irreversible (Stidl et al, 2018).…”

“…PEG-associated vacuolization in macrophages, predominantly within the reticuloendothelial system, is well documented with no detectable toxicological relevance (Kronenberg et al, 2013). However, several preclinical toxicology studies on approved PEGylated therapeutics provided evidence of vacuolation in renal tubule cells and epithelial cells of the choroid plexus (Stidl et al, 2016;Stidl et al, 2018). In one study, high doses of tumor necrosis factor binding protein (TNF-bp) conjugated with a 20 kDa PEG caused vacuolation of renal cortical tubular epithelium cells in rats, over a period of 3 months (Bendele et al, 1998).…”

Design and Preclinical Development of TransCon PTH, an Investigational Sustained-Release PTH Replacement Therapy for Hypoparathyroidism

“…To ensure an infusion‐like profile, PTH(1‐34) is transiently bound via the TransCon linker to a chemically inert, branched 40 kDa methoxypolyethylene glycol (mPEG) carrier that efficiently shields PTH from binding to the PTH1R and prolongs the peptide's circulation half‐life due to reduced renal clearance. PEG molecules have been shown to be nontoxic in animal species and humans and are used in a wide range of approved drugs . Through enzyme‐independent cleavage of the TransCon linker, controlled by physiological temperature and pH, active PTH is sustainably released with a linker release half‐life of approximately 2.5 days.…”

“…PEG molecules have been shown to be nontoxic in animal species and humans (10) and are used in a wide range of approved drugs. (11) Through enzyme-independent cleavage of the TransCon linker, controlled by physiological temperature and pH, active PTH is sustainably released with a linker release half-life of approximately 2.5 days. Here we describe the rationale for the design and development of TransCon PTH and present the pharmacokinetic (PK) and pharmacodynamic (PD) responses in rats and monkeys after single and repeat s.c. dosing for 4 weeks, as well as demonstrate proof-of-principle in a relevant disease model of HP.…”